The goal of this Multicenter ROt is to identify genetic risk factors that predispose individuals to amyotrophic lateral sclerosis (ALS). This RO1 is a continuation of collaborative efforts that have been ongoing since 1993, when this group identified the first ALS gene (the SOD 1 gene). Our Amyotrophic Lateral Sclerosis Genetics Collaborative Group (ALSGCG) has greatly extended the genetic knowledge of ALS by identifying loci on chromosomes 2, 9, 15, 16, 18, 20 and X using large autosomal dominant families; we have generated preliminary data for additional loci on chromosomes 1, 2, 7, 8, 17, 18, and 19 in smaller multiplex families. The ALSGCG represents the collaborative efforts of groups at Northwestern University Feinberg School of Medicine (NUFSM), Massachusetts General Hospital (MGH), Duke University Medical Center (DUMC), and Vanderbilt University Medical School (VUMS). We have collected the largest set of multiplex and singleton resources in the world and now have sufficient family material to begin gene discovery within these regions and test candidate genes as they become available. This RO1 is carried out at four sites. Site 1 (NUFSM) will use the locational candidate approach to identify the genes arising in the smaller multiplex families. This will include refining the linkage peaks using linkage analysis and testing candidate genes using allelic association studies. Site 2 (MGH) will use the locational candidate approach to identify the genes arising in the large autosomal dominant families using approaches similar to Site 1. It will also test the potential role of other motor neuron disease genes in ALS using an allelic association approach. The sites are supported by an Administrative Assistant from Northwestern, and a Genetic Epidemiology and Bioinformatics supported programs at DUMC and VUMS. Analysis of all data from the projects, including clinical, risk factor, pedigree, and genotypic data for NUFSM (Site 1) and MGH (Site 2) is carried out at DUMSC and VUMS analyses sites. Those also provide all linkage and allelic association analyses for Sites 1 and 2.